Chronic liver disease affects over one third of Americans and over one billion people worldwide. The annual cost associated with healthcare for these individuals exceeds $20 billion in the US alone. The most common etiologies are nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease, and chronic hepatitis B and C infections. Each of these is characterized by chronic hepatocellular damage, which in turn can lead to chronic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Although these causes of chronic liver disease all are very different, recent work by others and us suggests that each results in abnormalities in certain overlapping signaling pathways that, in part, mediate hepatocellular damage and the subsequent response to injury. The broad working hypothesis of this program project is that hepatocellular damage of varying etiologies, such as non-alcoholic fatty liver, alcohol, and other toxins, each leads to the development of chronic liver disease as a consequence of disrupting multiple overlapping pathways. The goal of this program project will be to understand collectively how these distinct signaling pathways within the hepatocyte integrate in order to drive the development of chronic liver disease. This hypothesis is conceptually novel and will be highly transformative to the field of hepatology in a manner that will stimulate new ways to fundamentally re-assess how certain liver diseases are understood and treated. This hypothesis will be tested through four individual research projects. Project 1 will test whether chronic inflammation and liver injury increases expression of the type 3 isoform of the inositol 1,4,5-trisphosphate receptor (InsP3R-3) in hepatocytes, and whether expression of this particular intracellular Ca2+ channel in turn is responsible for the impaired liver regeneration that occurs in chronic liver disease/cirrhosis. Project 2 will investigate which of th three isoforms of the InsP3R are in the mitochondrial-associated membranes (MAMs) of hepatocytes and how the different channel isoforms regulate mitochondrial and ER function. Project 3 will test how the stress-responsive MAP kinase phosphatase-1 (MKP- 1) is involved in the development of chronic hepatic inflammation and liver injury/repair and whether MKP-1 serves as central node to coordinate signals that promote liver repair. Project 4 will determine how O-GlcNAc transferase (OGT) transduces toxic insults into hepatocyte survival/death signaling, and how OGT deficiency contributes to the development of chronic liver disease. To help carry out these projects, core facilities will be established for molecular, cell and animal models, cell and tissue imaging, translational studies, and administration. These four projects will collectively provide a comprehensive investigation of how major signal transduction pathways in hepatocytes integrate to regulate the balance between growth and metabolism in liver health and disease. The results of these studies will have broad clinical implications for understanding the response to injury in a range of chronic liver diseases, including non-alcoholic fatty liver disease, liver disease resulting from exposure to alcohol and other hepatotoxins, and chronic viral hepatitis.